Bone mineral loss can result from a variety of causes including chronic conditions such as Cushing's syndrome, homocystinuria, hypercalciuria, and hyperprolactinemia. Alternatively, bone mineral loss is also associated with the normal aging process and accompanying loss of gonadal function in both females and males. Ostoeoporosis is characterized by significant reductions in bone mineral density, structural deterioration of bone tissue and enhanced susceptibility to bone fracture. This condition is generally preceded by osteopenia, a condition defined by the World Health Organization as a bone mineral density that is at least one standard deviation below that of an average 30-year old white woman. The frequency of these disorders increase with age in both males and females as does susceptibility to bone fractures, particularly of the hip.
In males, androgen deficiency is associated with a variety of symptoms including low bone mass. Indeed, the incidence of osteopenia, osteoporosis in this patient group is relatively high with a correspondingly high bone fracture rate. Testosterone plays a major role in bone mineral density (BMD); however, the effect of testosterone replacement on BMD remains controversial with several studies indicating that the effects of testosterone replacement on bone does not differ significantly from placebo (Snyder P J et al., J Clin Endocrinol Metab. 1999; 84:1966-1972). Other studies have reported a slight increase in BMD during testosterone replacement therapy which is thought to result from the conversion of testosterone into estradiol.
In the course of drug development, the inventors observed that treatment of men with isolated trans-clomiphene was accompanied by a significant reduction in CTX (C-terminal crosslinking telopeptide of type I collagen), an established biomarker of bone resorption, which is negatively correlated with BMD, presumably because reduced bone turnover provides a correspondingly increased opportunity for bone mineralization (Meunier and Boivin, Bone 21:373-377 (1997)). Thus, trans-clomiphene and its triphenylalkylene analogues provide a safe and effective class of compounds for the prevention and treatment of osteporosis and/or osteopenia.